Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy
Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the gene-is overexpressed in prostate tumors. We found up-regulated in human prostate tumors and expression inversely correlated...
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Veröffentlicht in: | Science advances 2024-02, Vol.10 (5), p.eadg7887 |
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Sprache: | eng |
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Zusammenfassung: | Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the
gene-is overexpressed in prostate tumors. We found
up-regulated in human prostate tumors and
expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr
. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress. |
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ISSN: | 2375-2548 2375-2548 |
DOI: | 10.1126/sciadv.adg7887 |